Development of photocaged DREADD agonists for high-efficiency, target-specific optical silencing of synaptic transmission - Genetically-encoded tools that provide researchers with a means to control neural activity in genetically-defined cell types are widely used to establish causal relationships between neural activity and behavior. Current tools for silencing synaptic output in a way that is restricted to anatomically-defined target nuclei in the brain suffer from technical drawbacks that limit their widespread use by the neuroscience community. Optogenetic silencing tools are either prone to artifacts or demonstrate limited efficacy. Although chemogenetic tools such as the hM4Di Designer Receptors Exclusively Activated by Designer Drug (DREADD) appear to be highly effective in multiple cell classes, anatomically-restricted silencing requires local infusion through guide-cannulas, which lacks temporal precision and perturbs ongoing behavior. To address these limitations, we are developing optochemogenetic tools in the form of “photo-caged” DREADD agonists that can be applied systemically in an inactive form and subsequently released in the brain with light to achieve site-specific synaptic silencing with high temporal precision using sub-second flashes of light. These reagents are designed to either be compatible with optical measurements of neural function involving fluorescent probes, or sensitive to sources of blue light that are commonly used by many labs for optogenetics experiments, which should allow for rapid and broad diffusion in the neuroscience community. We will rigorously validate new caged DREADD agonists using in vitro, ex vivo, and in vivo experimental paradigms, culminating in fiber photometry recordings and optochemogenetic modulation of behavioral responses to aversive and rewarding stimuli. This work builds on our recent advances using related photopharmacological probes that target opioid receptors. To maximize end-user uptake, performance criteria are determined through extensive consultation with the scientific community.
